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PREDICTION OF CYTOCHROME P450 3A INHIBITION BY VERAPAMIL ENANTIOMERS AND THEIR METABOLITES

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana

Verapamil inhibition of CYP3A activity results in many drug-drug interactions with CYP3A substrates, but the mechanism of inhibition is unclear. The present study showed that verapamil enantiomers and their major metabolites [norverapamil and N-desalkylverapamil (D617)] inhibited CYP3A in a time- and concentration-dependent manner by using pooled human liver microsomes and the cDNA-expressed CYP3A4 (+b₅). The values of the inactivation kinetic parameters k_inact and K_I obtained with the cDNA-expressed CYP3A4 (+b₅) were 0.39 min^-1 and 6.46 µM for R-verapamil, 0.64 min^-1 and 2.97 µM for S-verapamil, 1.12 min^-1 and 5.89 µM for (±)-norverapamil, and 0.07 min^-1 and 7.93 µM for D617. Based on the ratio of k_inact and K_I, the inactivation potency of verapamil enantiomers and their metabolites was in the following order: S-norverapamil > S-verapamil > R-norverapamil > R-verapamil > D617. Using dual beam spectrophotometry, we confirmed that metabolic intermediate complex formation with CYP3A was the mechanism of inactivation for all compounds. The in vitro unbound fraction was 0.84 for S-verapamil, 0.68 for R-verapamil, and 0.84 for (±)-norverapamil. A mechanism-based pharmacokinetic model predicted that the oral area under the curve (AUC) of a CYP3A substrate that is eliminated completely (f_m = 1) by the hepatic CYP3A increased 1.6- to 2.2-fold after repeated oral administration of verapamil. For midazolam (f_m = 0.9), a drug that undergoes extensive intestinal wall metabolism, the predicted increase in oral AUC was 3.2- to 4.5-fold. The predicted results correlate well with the in vivo drug interaction data, suggesting that the model is suitable for predicting drug interactions by mechanism-based inhibitors.

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